Adverse effects and drug interactions associated with local and regional anaesthesia

Systemic and localised adverse effects of local anaesthetic drugs usually occur because of excessive dosage, rapid absorption or inadvertent intravascular injection. Small children are more prone than adults to methaemoglobinaemia, and the combination of sulfonamides and prilocaine, even when correctly administered, should be avoided in this age group. The incidence of true allergy to local anaesthetics is rare. All local anaesthetics can cause CNS toxicity and cardiovascular toxicity if their plasma concentrations are increased by accidental intravenous injection or an absolute overdose. Excitation of the CNS may be manifested by numbness of the tongue and perioral area, and restlessness, which may progress to seizures, respiratory failure and coma. Bupivacaine is the local anaesthetic most frequently associated with seizures. Treatment of CNS toxicity includes maintaining adequate ventilation and oxygenation, and controlling seizures with the administration of thiopental sodium or benzodiazepines. Cardiovascular toxicity generally begins after signs of CNS toxicity have occurred. Bupivacaine and etidocaine appear to be more cardiotoxic than most other commonly used local anaesthetics. Sudden onset of profound bradycardia and asystole during neuraxial blockade is of great concern and the mechanism(s) remains largely unknown. Treatment of cardiovascular toxicity depends on the severity of effects. Cardiac arrest caused by local anaesthetics should be treated with cardiopulmonary resuscitation procedures, but bupivacaine-induced dysrhythmias may be refractory to treatment. Many recent reports of permanent neurological complications involved patients who had received continuous spinal anaesthesia through a microcatheter. Injection of local anaesthetic through microcatheters and possibly small-gauge spinal needles results in poor CSF mixing and accumulation of high concentrations of local anaesthetic in the areas of the lumbosacral nerve roots. In contrast to bupivacaine, the hyperbaric lidocaine (lignocaine) formulation carries a substantial risk of neurotoxicity when given intrathecally. Drugs altering plasma cholinesterase activity have the potential to decrease hydrolysis of ester-type local anaesthetics. Drugs inhibiting hepatic microsomal enzymes, such as cimetidine, may allow the accumulation of unexpectedly high (possibly toxic) blood concentrations of lidocaine. Reduction of hepatic blood flow by drugs or hypotension will decrease the hepatic clearance of amide local anaesthetics. Special caution must be exercised in patients taking digoxin, calcium antagonists and/or beta-blockers.     

Adverse drug reactions in pediatrics with a study of in-hospital intensive surveillance

A two-part prospective study of adverse drug reactions (ADRs) in Indian children was carried out at a teaching general hospital. Using an in-hospital intensive surveillance scheme (IISS) for the detection of ADRs, indoor patients of one of the two units in the pediatric ward were monitored daily for 6 months, with the other unit serving as a control group. A total of 347 patients were monitored, 2781 daily orders written and 24,474 doses of 96 different drugs given. Six patients suffered from ADRs (1.73%), and 1 reaction proved fatal (0.29%), while the control group reported only 1 ADR in the same time period. The frequency of ADRs (p < 0.001) and their resultant mortality in Indian children was less than that in a western prototype study. Though IISS showed a marked increase in ADR reporting, it was too cumbersome for routine use in our country. In the second part of the study, 40 cases of ADRs seen over 2 years were analyzed. Antimicrobials, especially sulphonamides, accounted for a high percentage of cases mostly as skin rashes and fairly severe reactions were common. Patients on anti-tuberculous and anti-convulsant drugs required prolonged supervision for late onset reactions.     

Intranasal immunization with attenuated live influenza vaccine in asthma

Attenuated live intranasal influenza vaccine ("Alice") was given to 20 asthmatics and 9 control subjects. Pulmonary function were performed before and after, with emphasis on tests of small airways function (using flow volume curves with air and a helium-oxygen mixture). In subjects with a low influenza A antibody titer, there was a 4-fold rise in titer to the vaccine, whereas those subjects with a high titer showed no rise. There were no significant changes in pulmonary function in any parameters measured, and no significant symptoms were reported. We have concluded from this study that "Alice" appears safe for use in asthma and was capable of producing an antibody titer rise in persons with low titers.     

Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis

BACKGROUND: The use of antidepressant medications and the resulting costs have increased dramatically in recent years, partly because of the introduction of selective serotonin reuptake inhibitors (SSRIs). An assessment of the clinical and economic aspects of SSRIs compared with the older tricyclic antidepressants (TCAs) was initiated to generate information for purchasers of these drugs as well as clinicians. One component of this study was an examination of the adverse effects associated with the use of these drugs. METHODS: Searches of bibliographic databases (for January 1980 through May 1996) and manual scanning of both peer-reviewed publications and other documents were used to identify double-blind, randomized controlled trials involving at least one SSRI and one TCA. For the study of adverse effects, only trials that had at least 20 patients in each trial arm and that reported rates of adverse effects in both arms were retained. In total 84 trials reporting on 18 adverse effects were available. Meta-analyses were undertaken to calculate pooled differences in rates of adverse effects. The question of whether the method of eliciting information from patients about adverse effects made a difference in the findings was also examined. Finally, differences in drop-out rates due to adverse effects were calculated. RESULTS: The crude rates of occurrence of adverse effects ranged from 4% (palpitations) to 26% (nausea) for SSRIs and from 4% (diarrhea) to 27% (dry mouth) for TCAs. The differences in the rates of adverse effects between the 2 types of drugs ranged from 14% more with SSRIs (for nausea) to 11% more with TCAs (for constipation). The results did not depend on the method of eliciting information from patients. There were no statistically significant differences between drug classes in terms of drop-outs due to adverse effects. INTERPRETATION: SSRIs and TCAs are both associated with adverse effects, although the key effects differ between the drug classes. Further explanation of the adverse effects and their relation to discontinuation of medication will require better studies involving prospective collection of quality-of-life data.     

Adverse drugs reactions associated with glaucoma medications

We undertook a non-concurrent prospective study of 191 Puerto Rican patients from August 1993 to April 1994. All patients had open angle glaucoma (OAG) (age ranged from 50 to 80 yrs; mean = 65 yrs). Patient's symptomatology associated to side effects of their glaucoma medicadons was reviewed. Incidence percent of ocular and/or systemic side effects per medication were: levobunolol 45.0%; betaxolol 42.0%; timolol 27.3%; pilocarpine 100%; dipivefrin 14.0%; and acetazolamide 250 mg 64.1%. Incidence percent of ocular and/or systemic side effects of topical beta-blockers used with concomittant medications were determined. Ocular side effects were more frequent in patients using levobunolol 44.2% than in those patients using betaxolol 42.0%, 8.5% of patients using levobunolol did report systemic side effects. No systemic side effects were reported by patients using betaxolol. Ocular side effects in patients using pilocarpine were frequent (100%); whereas the frequency of systemic side effects was low (6.1%). Systemic side effects were common in patients using carbonic anhydrase inhibitors. These results suggest that non-selective and cardio-selective topical Beta-blockers, differ in their ocular or systemic side effects.     

Adverse neuropsychiatric events associated with dexfenfluramine and fenfluramine

1. There is a large body of evidence indicating that fenfluramines damage brain serotonin neurons in animals. 2. Little is known about potential adverse neuropsychiatric consequences in humans associated with use of fenfluramines that could potentially be related to serotonergic dysfunction. 3. The authors now report numerous cases of severe and, sometimes persistent, neuropsychiatric syndromes associated with fenfluramine use. 4. Thirty one representative cases are presented and summarized in table form. 5. Several of the cases presented suggest long-lasting deleterious effects of fenfluramines on brain serotonin function. 6. Clinicians should be vigilant for disorders of mood, anxiety, cognitive function and impulse control in patients previously exposed to fenfluramines.     

Characterization of isolated adenovirus associated with acute lower respiratory infection in pediatrics

BACKGROUND: Acute respiratory infection (ARI) are a health care problem as the adenovirus (ADV) has shown to be one of the most frequent viral agents detected in children admitted for mild ARI in the authors medium. METHODS: Over a 7-year period (1988-1994) ADV isolated from patients under the age of 5, admitted for mild ARI in hospitals in the city of Buenos Aires (Argentina). All the strains were isolated in HEp-2 cell cultures from nasopharyngeal aspirates in which the presence of ADV was detected by indirect immunofluorescence with monoclonal antibodies. Antigenic characterization was performed by sero- and genome neutralization with restriction enzymes. RESULTS: The isolates corresponded to the genomic variants of ADV 7i, ADV 7c and to a greater number of ADV 7h. An increase was observed in the quantity of cases in the second half of the year. In the population studied, the most commonly infected were males (67.9%) and patients from 2 months to 1 year in age (89.2%). Sixty-six percent of the cases were severe infections with the length of hospitalization being greater than that of patients normally admitted for mild ARI by other virus and showed a high mortality. CONCLUSIONS: All the above events suggest that the genomic variants detected are highly pathogenic.     

Effectiveness of influenza vaccine in reducing hospital admissions in people with diabetes

By radioligand binding followed by Scatchard analysis, we characterized and quantitated the specific binding sites for bFGF on cultured trabecular meshwork cells obtained from freshly enucleated porcine eyes. We detected two binding sites: 1.67 x 10(4) +/- 5.75 x 10(2) high-affinity receptors per cell with a Kd of 33.4 +/- 7.90 pM, and 1.70 x 10(4) +/- 7.57 x 10(5) low-affinity binding sites per cell with a Kd of 3.84 +/- 1.41 nM. At low concentrations of 125I-bFGF (< 1.50 ng ml-1), binding was primarily determined by the high-affinity receptors and, at high concentrations (> 2.50 ng ml-1), binding was dependent on the low-affinity binding sites. By phase-contrast time-lapse video micrography and sequential photomicrography, we demonstrated that at a concentration of 1 ng ml-1, bFGF significantly stimulated the rate of mitosis of the trabecular meshwork cells in G0-phase compared with control cultures maintained in serum-free medium alone. Treatment with higher concentrations of bFGF did not reveal more potent effects on these cells. Our findings demonstrate that trabecular meshwork cells do possess low- and high-affinity receptors for bFGF and that bFGF induces these cells in vitro to re-enter the cell cycle. Because the low-affinity interactions of 125I-bFGF were reduced by 75% following pretreatment of the trabecular meshwork cells with heparinase, these sites represent cell-associated heparin-like molecules and heparan sulfate proteoglycans, and may control the bioavailability of bFGF to ocular tissues. Heparinase treatment also resulted in a 30% reduction in high-affinity binding, which may be secondary to the decreased low-affinity binding. This finding agrees with the well-established scheme for bFGF-receptor interaction. We conclude that bFGF at the concentration present in aqueous humor is capable of stimulating the mitotic activity of trabecular meshwork cells in vitro, suggesting a possible paracrine role of aqueous humour bFGF in vivo. The results obtained in this study, together with our previous findings on bFGF mRNA expression by trabecular meshwork cells and protein deposition in this tissue, also indicates that trabecular cells of the eye may utilize bFGF by an autocrine mechanism.     

Safety of influenza vaccine in heart transplant recipients

BACKGROUND: Influenza vaccine is recommended for heart transplant recipients, but its administration is often deferred because of anecdotal reports of rejection associated with the vaccine. We evaluated the safety of influenza vaccine in a group of stable heart transplant recipients over a 2-year period. METHODS: During the 1993 to 1994 influenza season, stable heart transplant recipients who had undergone transplantation a minimum of 1 year before study entry were randomized to vaccination with a single dose of influenza vaccine versus no vaccination. Routine endomyocardial biopsies and postvaccination influenza serologic studies were performed between 2 and 6 weeks after enrollment/immunization. During the 1994 to 1995 season, patients were given 2 doses of influenza vaccine, separated by 3 weeks; endomyocardial biopsies and serologic studies were performed between 2 and 6 weeks after the second immunization or enrollment (if control subject). Biopsy results were evaluated with respect to vaccine response, immunosuppressive regimens, and patient demographics. RESULTS: Eighteen patients were enrolled in the single vaccine trial and 10 in the booster vaccine trial. Four of 14 vaccine recipients had biopsy specimens consistent with International Society for Heart and Lung Transplantation grades 2 to 3A as compared with 1 of 14 control subjects (grade 2) (p = .326). All episodes of rejection in the vaccine recipients were asymptomatic and responded to a single course of treatment. Rejection was unrelated to the time from transplantation, doses of immunosuppression, age, or number of doses of or response to vaccine. CONCLUSIONS: Influenza vaccine can be safely administered to most heart transplant recipients but may be associated with low-level histologic rejection.     

Recent progress in live influenza vaccine development]

As live influenza vaccine, cold-adapted influenza virus vaccines (ca vaccine) have been extensively investigated in both the U.S and Russia. In Russia it has been licensed since 1988 and it is going to be licensed in the U.S. within a year or two. In general, the ca vaccine is more effective in seronegative population than the inactivated vaccine. In seropositive adult population, both are equally effective. In the elderly, inactivated vaccine is better than the live vaccine. In Japan, clinical trials were also conducted with the American ca vaccines. Although the efficacy was confirmed in limited locations, the vaccine could not be evaluated from the point of license approval because big epidemic did not occur during the studies.     

Adverse effects of cannabis

Cannabis is the most widely used illicit drug in many developed societies. Its health and psychological effects are not well understood and remain the subject of much debate, with opinions on its risks polarised along the lines of proponents' views on what its legal status should be. An unfortunate consequence of this polarisation of opinion has been the absence of any consensus on what health information the medical profession should give to patients who are users or potential users of cannabis. There is conflicting evidence about many of the effects of cannabis use, so we summarise the evidence on the most probable adverse health and psychological consequences of acute and chronic use. This uncertainty, however, should not prevent medical practitioners from advising patients about the most likely ill-effects of their cannabis use. Here we make some suggestions about the advice doctors can give to patients who use, or are contemplating the use, of this drug.     

Urticaria following varicella vaccine associated with gelatin allergy

An uncommon reaction to varicella vaccine has been urticaria. Based on two reports of urticaria believed to be due to gelatin in recipients of measles-mumps-rubella vaccine, we suspected gelatin as the cause of generalized urticaria in two children after varicella vaccination. Intradermal testing with gelatin yielded a wheal and flare reaction in both children. We conclude that children known to be allergic to gelatin should not receive Oka/Merck varicella vaccine (VARIVAX).     

Adverse effects of fertility drugs

Ovulation-induction agents are commonly used in the treatment of infertility in patients with or without ovulatory disturbances. These agents include clomifene, bromocriptine, gonadotrophin preparations and gonadotrophin-releasing hormone (GnRH) and its analogues. Each agent is associated with its own specific adverse effects. Although many of these adverse effects are benign and self-limited, some, in particular those effects associated with gonadotrophins, may be life-threatening. Commonly noted adverse effects encountered with the use of pharmacological agents to treat infertility include the following. Clomifene has been associated with hot flushes, multiple gestation, visual disturbances, cervical mucus abnormalities and luteal phase deficiency. Similarly, most of the adverse symptoms associated with bromocriptine are short-lived, such as nausea and postural hypotension. On the other hand, gonadotrophin therapy, even when used appropriately, may lead to the ovarian hyperstimulation syndrome (which is occasionally life-threatening) and a high incidence of multiple gestation. Pulsatile GnRH therapy maybe accompanied by similar adverse effects to those of gonadotrophins, but with a far lower incidence. With regards to the long term safety of these medications, the relationship between fertility drugs and epithelial ovarian cancer is controversial, and causality has yet to be proven. Indeed, a working knowledge of the many adverse effects associated with these medications is essential to any physician prescribing ovulation induction agents, in order to ensure maximum patient safety, compliance and understanding.     

Adverse effects of vigabatrin in Angelman syndrome

New antiepileptic drugs designed for enhancing GABAergic inhibition, such as vigabatrin (VGB) may be effective in Angelman syndrome (AS), because associated convulsions could be related to a reduced GABA-receptor density or receptor abnormality. From our preliminary experiences in four children with AS treated with VGB, we conclude that it may induce and increase seizures in patients with AS.     

Field investigation of influenza vaccine effectiveness on morbidity

Our objective was to evaluate influenza vaccine effectiveness during an influenza epidemic by means of a matched case-control study. The study was performed by 35 general practitioners who collected specimens for influenza virus testing from 610 patients who consulted for infectious syndrome: 168 (28%) were influenza-positive. Two designs were used for selecting controls to take into account the high incidence-rate of influenza-like illness and the various possible protective effects of the vaccine. A first disease-free control matched for age and sex was selected during the same week as the case. A second control matched for age and sex was selected at the end of the epidemic period, irrespective of disease history during the epidemic period. Upper and lower bounds of vaccine effectiveness can be derived from these case-control designs. After adjustment for chronic conditions and exposure to an index case, analysis of the matched-pairs whose case was influenza-positive showed, with the first group of controls, an influenza vaccine effectiveness of 68% (95% CI, 10% to 88%) and, in the second group, 53% (95% CI, -19% to 82%). Among the pairs whose case was negative for influenza, vaccine effectiveness was, respectively, 31% (95% CI, -17% to 59%) and 12% (95% CI, -47% to 47%). Vaccine effectiveness was highest for the H3N2 subtype whose vaccine strain was identical to that of the wild-type strain. The results suggest that influenza vaccine is effective in the field in preventing influenza morbidity.     

Effect of influenza vaccine on bronchoprovocation testing in normal subjects

A study of 55 nonasthmatic patients was undertaken to determine if recent influenza vaccination is a justifiable exclusionary criteria for bronchoprovocation testing. Healthy subjects without history of asthma and with negative methacholine challenge tests were given an intramuscular injection of killed influenza vaccine. Methacholine challenge testing was repeated 24 h later. While a statistically significant decline in FEV1 at 188 methacholine dose units was demonstrated (p < 0.018), this was not clinically significant; none of the 55 subjects converted a negative test to positive. We conclude that recent influenza vaccination is not a sufficient exclusionary criterion for methacholine challenge testing. Positive results in a patient recently vaccinated would still indicate asthma in the correct clinical setting.